Peptic ulcer disease (PUD) is a broad classification encompassing different types of gastric and duodenal ulcers, all of which are clinically characterized as an erosion of the mucosal lining in one or more areas of gastrointestinal tract. PUD does not occur when there is a balance between the aggressive factors and the defensive factors, manifesting only when the former factors become stronger than normal or when the latter factors weaken [1]. However, it is now accepted that Helicobacter pylori is present in more than 90% of duodenal ulcers and 70-80% of gastric ulcers [2]. PUD is therefore currently treated as an infectious disease also, cured with antibiotics.
Two of the major etiologies of peptic ulcer diseases are hyperacid secretion and infection by pathogenic H. pylori. For ulcers that are not caused by H. pylori, acid suppressive therapy alone is recommended either in the form of H2 receptor antagonists or proton pump inhibitors, beside simple use of acid neutralizing agents like antacids. However, antibiotic therapy should always be combined with acid suppressive therapy when treating H. pylori. Thus, the current therapeutic regimen for PUD with H. pylori involves two antibiotics, one antisecretory drug and one mucus coating agent (quadruple therapy) consisting of suitable four agents among amoxycillin, tetracycline, clarithromycin, metronidazole, and sucralfate or bismuth subsalicylate or subcitrate along with either of the two acid suppressing agents, H2 receptor blocker or proton pump inhibitor [3]. However, as with most drugs, a number of side effects are involved in their use. The adverse drug interaction of the cytochrome P450 system with H2 receptor blocker, hypersensitivity and damage of the liver by proton pump inhibitors, requirements of multiple doses of antacids to alleviate symptomatic-only relief, and the development of antibiotic resistance, coupled with ulcer recurrence problems [4] necessitate searching for better therapeutic management of PUD. For the development of effective anti ulcer agents having low toxicity, the inventors investigated a wide range of Indian medicinal plants. As a result, Woodfordia fruticosa flowers and its extracts were found to have low toxicity and excellent anti ulcer activity, and thus the present invention is completed, co-pending patent applications (WO 03/080095 PCTIN/03/0067) and US patent 20060040005, describing anti peptic ulcer activity of an extract of the plant flower W. fruticosa [5], delineating a new active principle, oenothein C.
Woodfordia fruticosa Kurz (syn. W. floribunda Salisb.) belongs to the family Lythraceae. English names that are frequently used for the plant are Fire Flame Bush and Shiranjitea. The local and traditional names are innumerable, especially in India, because of widespread traditional use. In India, a few popularly known names are Dhataki, Dawi, Jargi, Dhai, Harwari, Phulsatti, Dhavdi etc [6, 7]. The plant W. fruticosa is abundantly present throughout India, ascending up to an altitude of about 1500 meters. It is also present in a majority of the countries of South East and Far East Asia like Malaysia, Indonesia, Sri Lanka, China, Japan and Pakistan as well as Tropical Africa [8].
This plant has long been in regular demand amongst practitioners of traditional medicines throughout India and in different Southeast Asian countries. In India, it is a much-used medicinal plant in Ayurvedic and Unani systems of medicines [8-13]. Although all parts of this plant possess valuable medicinal properties, there is a heavy demand for the flowers, both in domestic and international markets specialized in the preparation of herbal medicines [14].
According to the Indian Systems of Medicine, this flower is pungent, acrid, cooling, toxic, alexiteric, uterine sedative, and anthelmintic, and useful in thirst, dysentery, leprosy, erysipelas, blood diseases, leucorrhoea, menorrhagia and toothache [8-19]. Many marketed drugs comprise flowers and other parts of the plant [11, 16-18]. The flowers are being used in the preparation of Ayurvedic fermented drugs called ‘Arista’s and ‘Asava’s [9, 19], and very popular in the Indian subcontinent as also in other south Asian countries [20, 21]. These flowers are capable of setting alcoholic fermentation as normally achieved by the use of pure yeast culture [9, 19]. A popular crude drug (called ‘Sidowaya’ or ‘Sidawayah’) of Indonesia and Malaysia chiefly contains dried flowers of W. fruticosa [22]. It is also an ingredient of a preparation used to make barren women fertile [22,23].
A systematic phytochemical investigation of W. fruticosa flowers described the characteristic presence of about 22% of tannin and also saponins in the aqueous and alcohol extracts [6]. Existence of triterpenoids besides steroids & steroid-like molecules, alkaloids and flavonoids was reported from the less polar solvent extracts [6, 7, 24, 25]. The presence of quercetin-3-rhamnoside, 2-hydroxy-1:4-naphthaquinone, polyphenols and traces of alkaloids was described [24-29]. Ellagic acid was isolated as the major polyphenol from the flowers and leaves [30]. Other polyphenols isolated include polystachoside, myricetin-3-galactoside and pelargonidin-3,5-diglucoside, the last one being the scarlet-red pigment that confers the beautiful colour to the flower [30]. A series of macrocyclic hydrolysable tannins—monomeric, dimeric as well as trimeric—have so far been isolated and their structures elucidated by spectral and chemical evidence [31-34].
Systematic pharmacological and biochemical investigations of the traditional remedies based on the plant and its parts substantiated many of the earlier empirical observations. Traditionally, fermented Ayurvedic drugs known as ‘Arishta’s are very popular in Southeast Asian countries. They are used for the treatment of a wide variety of diseases. In the preparations of many ‘Arishta’s, dried flowers of W. fruticosa are being used to enhance sucrose hydrolysis [35]. Immunomodulatory activity of the Ayurvedic drug ‘Nimba Arishta’, which contains W. fruticosa flowers, was demonstrated. Substantial increase in the inhibition of both human complement activity and chemoluminiscence generated by zymogen-stimulated human polymorphonuclear leukocytes was observed. Such increased biological activity was attributed to the immunoactive constituents released from the flowers of W. fruticosa [36]. An Ayurvedic medicine called ‘ Balarishta’, a drug of ‘Asava’ and ‘ Arishta’ group, contains W. fruticosa flower as one of the major constituents and is indicated in burning sensation (Agnimandya), weakness (Daurbalya) and rheumatic diseases (Vataja roga) [37]. This multi-ingredient Ayurvedic medicine, widely prescribed for the treatment of rheumatism, has exhibited anti-inflammatory activity against cotton pellet induced granuloma in albino rats. Activities of marker enzymes like acid phosphatase, GPT (glutamate pyruvate transaminase) and GOT (glutamate oxaloacetate transaminase) were significantly lowered by such Ayurvedic preparations, as compared with the reference anti-inflammatory drug phenylbutazone [38]. The aqueous extract of the flowers is recorded as a uterine sedative having usefulness in leucorrhea and menorrhagia [6, 39]. Anti-leucorrhoeic property of an Ayurvedic preparation containing W. fruticosa was shown to be effective in dysfunctional uterine bleeding [40].
New-biology based preclinical observations of some of the complex macromolecules, isolated from the flowers as well as leaves of W. fruticosa, are increasingly becoming available in recent time. Woodfordin C, a macrocyclic dimeric hydrolysable tannin isolated from the methanol extract of the leaves [33], showed remarkable inhibition of DNA topoisomerase II in vitro and antitumor activity in vivo [41]. Anti tumor activity of woodfordin C and oenothein B was evaluated in human carcinoma cell lines and in sarcoma 180 tumor-bearing ICR mice [42]. The macrocyclic ellagitannins inhibited the viability of S-180 tumor cells in vitro as well as in vivo. The cytotoxic effect in cell culture was demonstrated to be selective, and is perhaps expressed through potentiation of host-immune defense system, like activation of NK cells and/or augmentation of interleukin secretion [42, 43]. Woodfordin I has recently been shown to induce apoptosis in human chronic myelogenous leukemia (CML) K 562 cells. It suppressed proliferation of and induced apoptosis in these CML cells, as judged by cytomorphology, internucleosomal DNA fragmentation and externalization of phosphatidyl serine. Several naturally occurring polyphenolic compounds, including flavonoids, anthraquinones and certainly macrocyclic ellagitannins, isolated from W. fruticosa as well as from other medicinally useful plants, inhibited LPS-induced iNOS and COX-2 gene expression, implying their putative role in the management of inflammation [44, 45].
Patents describing the invention of anti ulcer agents from plant extracts like Psoralae corylifolia [46], Panax genus [47] or polyherbal preparations [48, 49] have been disclosed. The use of the plant Woodfordia fruticosa in various traditional systems of medicine, and also the effects of several components contained therein, as reviewed above, led to a few patents dealing with management of gynecological and hyperandrogenic disorders [50, 51] or bronchial asthma [52]. Skin whitening cosmetics containing W. fruticosa plant extract has been disclosed in a Japanese patent [53].
PUD is a specific pathological condition for which the acid HCl and the bug H. pylori are accepted to be the two major etiologies for the pathogenesis of gastroduodenal ulcers. Because of the failure of the current medical management after using even quadruple therapy (clarithromycin, amoxycillin, proton pump inhibitor or H2 receptor blocker, and sucralfate) in terms of ulcer recurrence and antibiotic resistance, a non-toxic and effective natural medicament is needed for the simultaneous treatment of gastric as well as duodenal ulcers.